Lewis Thomas (1995) in his justly famous book, described medicine as
`the youngest science'. Compared with physics and chemistry and even the
biological sciences, it was a relative new boy on the block. At the beginning
of the twentieth century, physicians prescribed empirical nostrums, few
of which had any biological basis and even fewer were evidence-based in
the way we understand this term nowadays. Now, at the beginning of the
twenty-first century, the notion of a scientific physic is no longer a
contradiction in terms.

However, the penetration of science into clinical practice has not been
uniform. There are still underdeveloped areas. Foremost among them is neurological
rehabilitation, a scientific adolescent which, as is the way with adolescents,
has precocious spending habits. The relative underdevelopment of the science
base of neurological rehabilitation is to be deeply regretted because neurodisability
is the most important healthcare challenge of the next few decades.

There are, for example, over 300 000 stroke survivors in the UK, coping
with often very severe levels of disability (Ebrahim and Harwood, 1999)
and stroke is but one of several common disabling neurological diseases.
The incidence of most of these diseases rises steeply with age. As the
population is ageing (Kinsella et al., 2000), unless we improve the effectiveness
of neurological rehabilitation, we shall see more, not less, neurodisability
in the future. This is despite advances in prevention and acute treatments,
for it has been shown that at present the gains resulting from preventative
measures are offset by the ageing of the population (Torvaldsen et al.,
1999).

HOW EFFECTIVE IS NEUROLOGICAL REHABILITATION?

Rehabilitation is difficult to define but, very briefly, it denotes
a package of measures designed to lessen the impact of disabling conditions
(Young, 1996). Damage to the right hemisphere may lead to a leftsided weakness
- an impairment. The question for rehabilitators is how to prevent this
weakness, this 'impairment', from translating into a 'disability', such
as an inability to walk, or, if this is not possible, how to prevent an
inability to walk from translating into dependence on others and limited
capacity to participate in everyday life, a 'handicap'.

We shall divide rehabilitation strategies into those that aim to prevent
the translation of impairments into handicaps, mainly by helping the patient
to adapt to them, which we shall name `higher-level' interventions, and
those that aim to reduce impairment, which we shall name `lower-level'
therapies. This distinction is clearly a gross simplification because some
rehabilitation strategies may have both kinds of effects. The two strategies
are illustrated in Figure 1.

The present state of affairs is illustrated by stroke. Organized stroke
care saves lives and reduces disability. Recent metaanalyses (Langhorne
et al., 1993; Stroke Unit Triallists' Collaboration, 2000) show that patients
who are managed within an organized stroke service are 30% less likely
to be dead or dependent at six months post-stroke. Even more encouraging,
it has now been shown that benefits are not transient. They are seen five
(Indredavik and Slordahl, 1997; Lincoln et al., 2000) and even 10 years
after the stroke (Indredavik et al., 1999). So much is clear. When it comes
to determining the specific contribution of rehabilitation, however, things
are less obvious.

There appears to be a distinctive contribution of the overall rehabilitation
package (as opposed to acute medical care and the prevention of medical
complications) to the observed improved mortality and outcome in terms
of dependency. The Stroke Unit Triallists Collaboration (2000) identified
multidisciplinary team working, commitment of all parties to the principles
of rehabilitation and early occupational therapy and physiotherapy as important
factors distinguishing organized stroke care from care in other, less favourable,
settings. An overview of studies of stroke rehabilitation found a weak
correlation between increased intensity of rehabilitation and patients'
improvement in terms of function in activities of daily living (Kwakkel
et al., 1997). However, generalization on the basis of the reported studies
was difficult because of their poor methodological quality.

The picture becomes even murkier when we try to determine the respective
contribution of `higher-level' and `lower-level' components of the rehabilitation
package to the overall effectiveness of rehabilitation. For example, Walker
and colleagues (1999), in a study of stroke patients not admitted to hospital,
found that modest input from an occupational therapist (approximately five
visits over a six-month period) produced significant improvement in outcome
in terms of activities of daily living. The intervention was `higher-level'
and consisted of occupational therapy designed to increase independence
in personal and instrumental activities of daily living. By contrast, when
Lincoln and colleagues (1999) examined the effect of increased intensity
of 'lowerlevel' upper limb rehabilitation, using interventions based on
the Bobath concept (the one most widely used in the UK; Sackley and Lincoln,
1996; Davidson and Waters, 2000) they found that patients who received
additional, more intensive therapy fared no better either in terms of activities
of daily living or specific measures of arm function than those who received
the standard treatment. The picture is not entirely clear, however, as
post hoc analysis of the data suggests that additional therapy consisting
of repetitive functional activities might improve function in the patients
who demonstrated milder upper limb function (Parry et al., 1999). Lower-level
interventions were also investigated by Kwakkel et al. (1999), who reported
a beneficial effect of increased intensity of activity and muscle strengthening,
which included functionally orientated therapy directed at upper and lower
limbs. However, the implications of the study for the generality of stroke
patients are uncertain because only 3% of patients were recruited and these
workers did not measure impairment A recent systematic review of publications
on physical therapies to improve movement performance and functional ability
post-stroke (Pomeroy and Tallis, 2000) found that a few lower-level techniques
seemed to be effective, at least in the studies which met the review criteria.
Even though there was sufficient evidence to justify further investigation,
there was no compelling evidence that any single technique had a major
sustained effect in reducing impairments. Most of the primary studies were
of poor quality.

None of the above should be taken to imply that therapy is not overall
beneficial. However, the lack of major effects seen in research on clinical
experience from lowerlevel techniques designed to reduce impairments is
worrying because the gains to be had from higher-level interventions designed
to help patients cope with impairments, although not insignificant, could
be limited even if the best method of delivering the current package of
care is identified (the overriding preoccupation of much health services
research). If impairment can be reduced then the potential for recovery
of function is greater. The challenge is to build on what we can presently
achieve in reducing dependency through helping patients to adapt to impairments
by trying to reverse impairments. For illustrative purposes the present
paper focuses on physical therapies for motor problems.

NEUROLOGICAL REHABILITATION: NOT YET A MATURE SCIENCE

Rationale

In clinical practice most physical therapies to restore movement have
been developed through clinical experience and have a tendency to be based
on now outdated beliefs about what does and what does not promote recovery.
Often, these rationales lead to recommendations that do not withstand further
examination. For example, the predominant physiotherapy concept in the
UK, the Bobath concept, discourages self-propelled wheelchairs, on the
basis that they increase spasticity, increase unwanted associated movements
and increase abnormalities of posture, such as asymmetry (Cornell, 1991).
This claim has been examined directly by use of an instrumented seat which
records the distribution of the pressure of the buttocks on a wheelchair
seat. It was not possible to show an increase in seated asymmetry as a
result of wheelchair use. Other underlying rationales to practice, such
as the proposed adverse effect of progressive resistive exercises to reduce
muscle weakness are challenged by research findings (Miller and Light,
1997; Brown et al., 1997). A first step towards more effective treatment
of impairments, therefore, will be a critical evaluation of current rationales
for treatment.

Content of therapies

Of equal concern is the vagueness with which physical therapies tend
to be specified, even in the most scrupulously conducted trials. This is
understandable, perhaps, because of the complexity of such therapies. This
complexity has been examined in some detail. It was found that not only
did physiotherapists do many different things, for example 31 ploys in
mobilizing patients with higher-level gait disorders (Mickelborough et
al., 1997) and no less than 175 types of intervention in the prevention
and treatment of post-stroke shoulder pain (Pomeroy et al., 2001). There
was little consensus as to the 'correct' intervention to use.

Characterization of the target population

The deficits being treated are rarely clearly specified. Stroke patients,
for example, tend to be grouped together for trials or, at best, stratified
according to very broad categories of severity. For example, a recent comparison
of Bobath approaches and Movement Relearning Programme approaches for stroke
classified patients only according to sex and side of stroke (Langhammer
and Stanghelle, 2000). If, as seems highly likely, therapy should be tailored
to the type of deficits, it is essential to specify the nature of those
deficits and to address relatively homogeneous groups of patients in trials,
in order to avoid missing an effect on subgroups who may have benefited,
even though the group as a whole did not. We do not, after all, evaluate
drugs for otherwise unspecified 'fever'. Unfortunately, as yet there is
no clear idea of a suitable taxomony of lesions or impairments for defining
inclusion in clinical trials, something which became apparent in a recent
trial of treadmill retraining for patients with higher-level gait disorders
in cerebral multi-infarct states (Liston et al., 2000). A post hoc analysis
of the results suggested that patients with gait ignition or initiation
problem should be distinguished from those with equilibrium problems, with
the focus on the former.

Outcome measures

Although trials use measures of movement and functional ability which
are clinically appropriate these give limited information about the mechanisms
which underlie clinical change. This information is important for evaluating
attempts to reverse impairments, as it gives insight into what, if anything,
has actually happened to the patient's nervous system.

Some studies make an attempt to report and even quantify neurological
changes, but even where it is potentially illuminating, this is often unreliable.
For example, it has recently been found that the clinical assessment of
muscle tone by use of a simple three-point scale: flaccid, normal and spastic,
proved unreliable even in the hands of expert physiotherapists and doctors
(Pomeroy et al., 2000). A novel visual analogue scale proved equally unreliable.
Ironically, a paper published in the same issue of the same journal, came
to the opposite conclusion about the reliability of clinical measures of
muscle tone (Gregson et al., 2000), although the different outcomes have
more to do with which statistical tests are appropriate to analyse agreement
between raters (Pomeroy et al., 2001).

Understanding the effects of physical therapies on the nervous system
requires utilization of neurophysiolological tests. In the neurological
rehabilitation literature, only a small number of studies have done so.
In the absence of appropriate tests, trials are comparable to studies of
a putative hypotensive drug and assessing its effect in terms of quality
of life without seeing whether it actually lowers the blood pressure. Put
another way, it seems as if physical therapies have moved to the stage
of pragmatic real world trials without passing through the first phase
- essential for a truly scientifically based therapy of explanatory trials.

THERAPEUTIC IMPLICATIONS OF THE SOFT-WIRED SYSTEM

For a long time pessimism and the emphasis on adaptation to as opposed
to reduction of impairment, seemed to be justified by the observation that
neurones exhibit limited capacity for regrowth in the adult brain. If the
brain were hard-wired, death of neurones meant irreversible loss of function.
Now, things look more cheerful. In the `soft-wired' nervous system, function
depends on organization (connectivity); reorganization does not always
require regrowth, and so function may be restored without major regrowth.
New methods of imaging the activity and connectivity of the living brain
have been revelatory, showing a nervous system that is a less fixed structure
than was previously thought.

There are many examples of neuroplasticity revealed by functional imaging,
both of normal subjects acquiring new skills and of impaired individuals
recovering from brain damage (for an excellent review, see Hallett et al.,
1998). Hamdy and colleagues (1996), for example, used transcranial magnetic
stimulation to map the cortical representation of swallowing in normal
subjects, non-dysphagic stroke patients and dysphagic stroke patients.
The cortical map of swallowing in a patient who was dysphagic at presentation
and who by three months post-stroke had recovered swallowing showed dramatic
changes. The initial dysphagia was explained by the near complete absence
of cortical representation of swallowing, due to ischaemic damage. This
area in the left hemisphere had been damaged by the stroke. Subsequent
recovery from dysphagia was explained by the huge expansion of the cortical
representation of swallowing in the opposite hemisphere.

We need to know how to assist this process. To do this a better understanding
of the drivers to reorganization is needed, at both the microscopic (dendritic
and synaptic) and macroscopic (cortical maps) levels. Here, another insight
is crucial: functional activity-associated afferent input appears to be
an important driver to reorganization that may bring about functional recovery.
As expressed by Buonomano and Merzenich (1998) in relation to the cortex:
experience drives reorganization. This is not entirely straightforward,
as the size of cortical representation may be associated more with the
process of skill acquisition than with the use of acquired skills (Pascual-Leone
et al., 1994).

However, if afferent inputs associated with normal activity are the
most potent influences maintaining or restoring functional organization,
there is a problem for impaired patients, as illustrated in Figure 3. Loss
of normal function deprives the brain of afferent information with the
resulting attenuation of precisely those experience and activity-based
signals that drive adaptive reorganization as well as permitting maladaptive
reorganization, commonly expressed in spasticity. There is, therefore,
a vicious circle which has to be broken.

Promoting recovery

There are several possible strategies, including the use of prosthetic
inputs such as electrical stimulation (Glanz et al., 1996), assisted and
independent activity giving more 'natural' inputs (Potempa et al., 1995;
Dean and Shepherd, 1997; Visintin et al., 1998) and, an approach that has
attracted much recent attention, constraint-induced therapy, which involve
encouraging the use of a paretic arm contralateral to the stroke loss by
constraining the use of the nonparetic arm (van der Lee et al., 1999).

Electrical stimulation

Excitatory electrotherapy aims to bring about an immediate effect, such
as the contraction of a muscle or the stimulation of a excitatory or inhibitory
pathway in the nervous system. Cerebellar stimulation was introduced over
30 years ago in the hope of reducing spasticity in cerebral palsy on the
basis that the output from the cerebellum was largely inhibitory (Cooper,
1973). Lateral popliteal nerve stimulation (Burridge et al., 1998) and
forearm stimulation (Chae et al., 1998) have also been used. More recently,
there has been considerable interest in deep brain stimulation for patients
with Parkinson's disease (Benabid et al., 1991). Finally, programmed muscle
stimulation, as in paraplegic walking devices (for example, Marsolais and
Kobetic, 1988) has also been used in clinical practice, though its place
still remains uncertain after 20 years of research and development. With
the exception of thalamic stimulation for Parkinson's disease and functional
electrical stimulation for selected patients with foot drop, the results
have been largely disappointing and the overall message seems to be that
excitatory stimulation is probably not going to play a major part in the
management of patients with severe neurological disease. Patients do not
like being encumbered with equipment, and find it inconvenient to put on
and take off. There are also considerable technical problems. Moreover,
knowing what to stimulate in the case of more complex lesions is not very
clear. What is needed is the kind of stimulation that brings about functional
reorganization: neuroculture rather than 'puppetry'. For this, chronic
stimulation designed to bring about plastic change might be more promising,
such as contingency stimulation for unilateral spatial neglect which has
been shown to produce specific changes in measures of spatial neglect (Prada
and Tallis, 1995).

If what maintains or restores functional organization of the nervous
system is the information arising from normal activity, it might be expected
that quasi-natural stimuli would be more effective than, uniform frequency
electrical stimulation. Over a 10-year programme of work, this notion was
explored using a rather simple and much less ambitious example of excitable
tissue, namely muscle. Muscle is a good place to start because it exhibits
extraordinary activity-related plasticity. By use of analytical electromyographic
techniques, Kidd and Oldham (1988) tracked the firing patterns of individual
motor units. They observed the changes of those patterns at the extremity
of exertion, in other words, under precisely those conditions in which
muscles become stronger and more fatigue-- resistant. The firing pattern
of an extremely fatigued motor unit is a mixture of fast and slow frequencies.
This pattern was loaded into a programmable stimulator and used to treat
wasted muscles. The effect was measured in terms of both muscle strength
and fatiguability. This technique was sometimes effective, as in patients
with wasting and weakness of the first dorsal interosseus associated with
rheumatoid arthritis (Kidd and Oldham, 1988) and, less predictably, with
ulnar nerve palsy (Petterson et al., 1994), but was much less effective
for large muscle, such as the quadriceps (Howe et al., 1995).

The conclusion to be drawn is that we are not yet able to mimic electrically
the kind of information that excitable tissue needs in order to enhance
its ability to undergo adaptive reorganization after injury.

Assisted activity

Another way of inputting afferent information is, of course, the time-honoured
approach of assisted activity. This lies at the heart of many physical
therapy interventions and, as mentioned above, modest benefits are seen
with some exercise-based therapies (Pomeroy and Tallis, 2000). Treadmill
retraining, a form of assisted walking, has been widely investigated in
recent years for patients with hemiparesis (for example, Visintin et al.,
1998; Hesse et al., 1999) and with higher-level gait disorders due to cerebral
multi-infarct states (Liston et al., 2000). Benefits are seen consistently.

The attractiveness of prosthetic inputs such as electrical stimulation
is that they can be given in large quantities 24 hours a day but they do
not closely match what the healthy system normally receives. The attractiveness
of natural inputs from assisted activity is that they are `of the right
kind'; however, they can be given in doses that could be regarded as homeopathic.
What happens during 30 minutes' uninterrupted activity on, say, a treadmill
is a minute proportion of the normal activity in a normal day. Upper limb
rehabilitation therapy may last only a proportion of 30 minutes, and the
number of movements falls well short of the number of movements made by
a normal limb in a average day. There are, however, many added advantages
to active participation as opposed to passive stimulation. They seem to
carry more centrally active information because the patient attends more
to what is happening and it has been clearly demonstrated that attention
promotes reorganization (Robertson et al., 1997).

It seems as if we can roar at the nervous system in the wrong language
or whisper to it inaudibly in the right language. Put another way, we seem
to be able to give patients large doses of weak medicine through prosthetic
inputs, or small or homeopathic doses of strong medicine through natural
inputs. An exception to this may be constraint-induced therapy a form of
exercise-based therapy in which the drive to increased activity of affected
limb is continuous and sustained and the consequent increased afferent
input is natural.

Constraint-induced therapy

Constraint-induced therapy is based on experimental evidence of the
effects of 'forced' use in monkeys and has progressed through a series
of small studies in chronic stroke patients which have found beneficial
and sustained effects (for example, Taub et al., 1993; Liepert et al.,
1998). The technique involves constraining the arm on the stronger side
to encourage or drive the use of the weaker side. However, a recent single-blind
randomized clinical trial found that, although constraint-induced therapy
improved upper limb function more than intensive bimanual training, an
effect that was maintained one year after treatment, the difference between
the two treatments was smaller than what was considered to be the minimal
clinically important difference (van der Lee et al., 1999). Nevertheless,
further characterization of stroke patients suitable for this approach
might be indicated, as a post hoc analysis suggested that stroke patients
with sensory disorder or unilateral neglect might be more likely to benefit
(van der Lee et al., 1999).

In practice, constraint-induced therapy is an amalgamation of several
elements: the constraint, repetitive functional exercise and increased
attention to the weak limb. Indeed, one explanation for the lack of clinically
significant effect found in the study reported by van der Lee and colleagues
(1999) is that constraint-induced therapy was compared to bilateral exercise.
The active ingredients might therefore be repetitive functional exercise
and increased attention to the paretic limb rather than the constraint.
This suggestion receives some support from a before and after study of
16 chronic stroke patients who showed significant increases in motor function
of the upper limb after six weeks' bilateral arm training performed for
one hour, three times a week (Whitnall et al., 2000). This effect was maintained
two months after the end of treatment.

In addition, even though studies of constraint-induced therapy in chronic
stroke patients have found that improvements in function of the weaker
upper limb are associated with cortical reorganization, similar changes
have been found in studies that investigated cortical maps and brain activity
on at least two separate occasions after stroke, but did not directly relate
these to therapy given in the intervening period. The changes related to
constraint-induced therapy were:

* Increase in size of motor representation and in amplitude of motor
evoked potential for the paretic target muscle in the lesioned hemisphere
(Kopp et al., 1999).

* Relocation of cortical activity during paretic finger movements from
the lesioned to the non-lesioned hemisphere (Kunkel et al., 1999).

* Equalization of size of the cortical representation area for the paretic
target muscle in the lesioned and non-lesioned hemisphere six months after
treatment (Blanton and Wolf, 1999).

The changes related to the unspecified therapy and improvements in the
function of the weaker side or good motor recovery were:

Progress requires modelling studies to be undertaken to determine the
effects of the elements of constraint-induced therapy, singly and in interaction,
before undertaking randomized controlled trials.

THE CHALLENGE OF THE FUTURE

In summary, we need to find ways of administering appropriate and adequate
inputs to promote adaptive plasticity. There is much work to be done in
defining those inputs and in determining the necessary doses and the appropriate
timing, especially since there is some evidence from animal studies that
suggests that enhanced activity in the first week after stroke, far from
promoting reorganization, may actually threaten a vulnerable ischaemic
penumbra around a core lesion and it may result in increasing the size
of an infarct (Kozlowski et al., 1996).

It might be objected that new approaches to neurological impairment,
such as drugs to promote regrowth, or cellular implants may have more to
offer than the most carefully designed activities. Most recent research,
however, supports the clinical intuition that if neural circuitry is required
rather than neural tangles then you cannot bypass the need for information
arising out of normal activity. Feeney and Sutton (1998) noted that the
beneficial effect of drugs such as amphetamines were not seen in restrained
animals. Mattson and colleagues (1997) reported that implants of fetal
neocortical cells produce behavioural benefits in lesion animals only in
enriched environments, and Wenk et al. (1999) found that growth factor
inhibition as well as stimulation was essential for recovery. In other
words, it is not merely the drive to regrowth and reorganization that matters
but also the control of growth and reorganization and this can come only
from afferent information relating typically to normal activity. We cannot
therefore evade the task of defining inputs of the right kind: what dose
of what kind of afferent activity for what lesion at what time.

CONCLUSION

It is important not to be too pessimistic about the current state of
neurological rehabilitation. As we have seen, organized stroke care does
reduce disability and this is at least in part due to rehabilitation. Indeed,
we could save even more people from becoming dependent if organized stroke
care were universally available (Ebrahim and Redfern, 1999). Moreover,
it would be inappropriate to dismiss the neurorehabilitation research carried
out so far.

The message emerging from the present paper, however, will be sufficiently
obvious: determining the right inputs to drive neuroplasticity will be
very difficult. We have a huge hill to climb if we are going to make further
progress in neurological rehabilitation; if, in particular, we are going
to exploit in neurotherapy the new understanding coming from basic neuroscience.
Even in the simple model of muscle, remote from the complexities of stroke,
it has proved very difficult to translate advances in theoretical understanding
into practical treatment. We need integrated research programmes in which
meaningfully defined lesions are treated with well-characterized, biologically
plausible, therapies and outcomes are assessed by use of genuinely informative
neurophysiological and clinical measures.

This is a formidable research agenda. How is it going to delivered?
First, we need a massive scaling-up of research efforts. The contrast between
the amount of investment in developing drug treatments and that deployed
in developing physical therapies is staggering, whereas neurological rehabilitation
practice has adult spending habits, neurological rehabilitation research
certainly does not. Second, our efforts will have to be better co-ordinated;
there must be an end to neurological rehabilitation research as a cottage
industry. We will not achieve one-tenth of the agenda if we continue to
order our affairs in the haphazard way we do at present, pinning hopes
of advance on a few scattered enthusiasts. Progress comes from making mistakes
as quickly as possible and the rate at which the few enthusiasts have got
things informatively wrong or right over the last 20 or 30 years is simply
not fast enough. Finally, and most importantly, we need to have clinicians
and basic scientists working more closely together, currently the dialogue
between neurotherapists and neuroscientists is too intermittent.

If we read the message arising from the current state of the art correctly,
there is an outside chance that within a few decades we will have genuine
science-based therapies rather than the hit and miss remedies that we offer
our patients at present. Then, we should truly be able to build on what
we offer our patients, by adding the benefits of reversing impairments
to our current strategy of helping them to adapt to them.